A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe
A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe
Nacer Abbas+, Christoph B. Lücking+, Sylvain Ricard1, Alexandra Dürr, Vincenzo Bonifati2, Giuseppe De Michele3, Sandrine Bouley1, Jenny R. Vaughan4, Thomas Gasser5, Roberto Marconi6, Emmanuel Broussolle7, Christine Brefel-Courbon8, Biswadjiet S. Harhangi9, Ben A. Oostra10, Edito Fabrizio2, Georg A. Böhme11, Laurent Pradier11, Nick W. Wood4, Alessandro Filla3, Giuseppe Meco2, Patrice Denefle1, Yves Agid, Alexis Brice*, the French Parkinson’s Disease Genetics Study Group§ and the European Consortium on Genetic Susceptibility in Parkinson’s Disease¶
INSERM U289, Hôpital de la Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France, 1Genomics Department, Rhône-Poulenc Rorer, 91006 Evry Cedex, France, 2Dipartimento di Scienze Neurologiche, Università ‘La Sapienza’, 00185 Rome, Italy, 3Dipartimento di Scienze Neurologiche, Università Federico II, 80131 Naples, Italy, 4Institute of Neurology, Queen Square, London WC1N 3BG, UK, 5Neurologische Klinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, 81377 Munich, Germany, 6Divisione di Neurologia, Ospedale Misericordia, 58100 Grosseto, Italy, 7Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, 69003 Lyon, France, 8Service de Pharmacologie-Centre d’Investigation Clinique, INSERM U455, CHU de Toulouse, 31073 Toulouse, France, 9Department of Epidemiology and Biostatistics, Erasmus University Medical School, 3000 DR Rotterdam, The Netherlands, 10Department of Clinical Genetics, Erasmus University, 3015 GE Rotterdam, The Netherlands and 11CNS Department, Rhône-Poulenc Rorer, 94400 Vitry, France
Received December 14, 1998;Revised and Accepted January 20, 1999
Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson’s disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designatedparkin. We have analysed the 12 coding exons of theparkingene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 ± 12 years, but onset up to age 58 was observed. Mutations in theparkingene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in theparkingene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.
Parkinson’s disease (PD) is a frequent neurodegenerative disorder with a prevalence close to 2% after age 65 (1). The major signs of the disease are tremor, rigidity and bradykinesia associated with a good response to treatment with levodopa. The disorder is caused by a massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. The aetiology of the disease is still unknown, but the existence of genetic susceptibility factors is strongly suspected (2). Several familial forms of PD with autosomal dominant transmission have been reported. Mutations in the [alpha]-synuclein gene on chromosome 4q21-q23 were described in several PD families with early onset and rapid disease progression (3,4). However, [alpha]-synuclein is a minor locus, found only in a subset of families with dominant transmission (5-7). A second susceptibility locus was localized on chromosome 2p13 in German families with autosomal dominant PD (8). Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544) was first described in Japan (9,10). AR-JP patients show the typical signs of PD, but they are associated with: (i) early onset, typically before the age of 40; (ii) dystonia at onset; (iii) diurnal fluctuations; (iv) slow disease progression; and (v) early and severe levodopa-induced dyskinesias. In a few cases, neuropathological examination has shown a massive loss of dopaminergic neurons in the pars compacta of the substantia nigra, but the absence of Lewy bodies, the histopathological hallmark of PD (9,11,12). Recently, the AR-JP locus, designated PARK2, was mapped to chromosome 6q25.2-27 in consanguineous Japanese families (13). Subsequently, linkage analyses, our own (14) and others’ (15), have demonstrated the existence of non-Japanese PARK2 families in Europe, the USA and the Middle East. Homozygous deletions of one or more microsatellite markers in three AR-JP families greatly reduced the initial 17 cM candidate interval (14-16). Very recently, Kitada et al. identified a novel gene, designated parkin, in which homozygous deletions of either exon 4 or exons 3-7 were detected in four Japanese families with AR-JP (17). The parkin gene has an estimated genomic size of 500 kb and consists of 12 coding exons with an open reading frame of 1395 bp. The corresponding protein, parkin, composed of 465 amino acids, shows moderate homology to ubiquitin at the N-terminus and contains a RING-finger motif at the C-terminus (17). Subsequently, homozygous deletions of exon 3 were found in two European families and of exons 8-9 in one Algerian family (18). To date, two point mutations in the parkin gene have been reported in two Turkish AR-JP families (19).
In order to determine the frequency and the diversity of mutations in the parkin gene as a cause for the AR-JP phenotype in Europe, we amplified the 12 coding exons of the parkin gene in 35 families with autosomal recessive early onset parkinsonism and sequenced the exons in the patients that did not show homozygous exon deletions.
A homozygous deletion of exon 4 was detected in all three patients of an Italian family (IT-005), previously shown to be homozygous for four markers at the disease locus (14; Fig. 1).
Figure1. Homozygous exon 4 deletion in the patients of the Italian family IT-005. Bands (PCR products of the indicated exons) correspond to the numbered individuals. Black squares (men) and circles (women) represent affected individuals. Age at onset (in years) is given above the patient’s symbol. Slashed symbols indicate deceased individuals. Ex, exon; i, inner; o, outer.
In the index patients from the 34 families that did not show homozygous exon deletions, sequence analysis of all coding exons, including the exon-intron boundaries, revealed 11 sequence variations in exons and three in introns (Table 1). Eight of the exonic variations co-segregated with the disorder in the families (Fig. 2) and were not detected in 110-166 control chromosomes (Table 1). They are therefore most probably causative mutations (Fig. 3).
Figure2. Families with point mutations in the parkin gene. Complete co-segregation of the mutations with the disease is shown. Black squares (men) and circles (women) represent affected individuals with age at onset (in years) indicated above the patient’s symbol. Slashed symbols indicate deceased individuals. The numbers of unaffected sibs not analysed are given in diamonds. For each mutation the genotype of the family member is indicated (+/+, homozygous wild-type; +/-, heterozygous for the mutation; -/-, homozygous for the mutation). Under each genotype, the detection data are shown. PAGE: electrophoregrams with allele sizes in bp; ASO: autoradiograms of mutated and wild-type allele; restriction assay: PCR products after digestion with the appropriate restriction enzyme. Fragment lengths in bp are indicated. Mut, mutated; nd, age at onset not determined, as patient is unaware of her clinical signs.
Figure3. Point mutations in the parkin gene. The coding sequence of the gene with its 12 exons is represented as a bar. Exons are numbered 1-12. The eight causative point mutations are positioned according to their effect on the protein (truncating versus missense). The ubiquitin-like domain and the RING-finger motif are hatched. For the mutations Thr415Asn and Trp453Stop the putative phosphorylation sites (P) and the N-myristoylation site (M), respectively, are indicated. UTR, untranslated region.
Four mutations resulted in truncated proteins: 202-203delAG in exon 2 of families IT-020 and UK-086 (from the UK); 255delA in exon 2 of family FR-096 (from France); 321-322insGT in exon 3 of family FR-119; 1459G->A (Trp453Stop) in exon 12 of family IT-006. These mutations were homozygous in patients, except for the 202-203delAG mutation in families IT-020 and UK-086.
Four missense mutations were observed. In family IT-020, a heterozygous 584A->T transversion (Lys161Asn) in exon 4 was detected in addition to the 202-203delAG mutation described above. Segregation analysis showed that the two mutations were located on different alleles and that all patients were compound heterozygotes (Fig. 2). Two other heterozygous, non-conservative amino acid changes were observed in exon 7 of patients from families DE-012 (from Germany) and IT-015: 867C->T (Arg256Cys) and 924C->T (Arg275Trp), respectively. Finally, a homozygous 1345C->A transversion in exon 11 of all patients from family IT-014 resulted in a conservative (Thr415Asn) amino acid change.
In three of the families with heterozygous mutations (UK-086, DE-012 and IT-015), no complementary heterozygous mutation could be detected by sequencing.
Three of the 11 exonic sequence variations were detected in control chromosomes and were thus classified as polymorphisms (Table 1). They resulted in two conservative and one non-conservative amino acid change. A 601G->A transition (Ser167Asn) was heterozygous in only one of the two affected members of family FR-730 and on 1% of the control chromosomes (2/166). In addition, it was found in all sibs, including an unaffected, of family IT-020, in which the disease is already explained by the compound heterozygosity of two causative mutations (see above). A 1239G->C transversion (Val380Leu) in exon 10 was either heterozygous or homozygous in 11 families (IT-014, IT-020, IT-058, FR-017, FR029, FR-038, FR-096, FR-431, UK-006, UK-086 and DE-022). It did not segregate with the disease and was found on 16% of control chromosomes. A 1281G->A transition (causing the non-conservative Asp394Asn change) in exon 11 was heterozygous in the index patient of family UK-046 and heterozygous or homozygous on 7% of control chromosomes.
The nucleotide numbers are given according to the cDNA sequence published in the DNA Data Bank of Japan (DDBJ accession no. AB009973). Ex, exon; PAGE, polyacrylamide gel electrophoresis; ASO, allele-specific oligonucleotide. aCausative mutations are given in italic.
Variants in introns 2, 3 and 7 (IVS2+25T->C, IVS3-20C->T, IVS7-35A->G) were located at a distance from the splice sites. These polymorphisms were detected on control chromosomes at a frequency of 19, 10 and 27%, respectively (Table 1). Finally, a homozygous 768C->T transition (Pro223Ser) was found in all individuals sequenced, suggesting that 768C was an error in the initial cDNA sequence (17).
According to the PROSITE program, the conservative amino acid change Thr415Asn is located within the consensus sequence for putative phosphorylation sites of cAMP- and cGMP-dependent protein kinases (KKTT) and protein kinase C (TTK). The truncating nonsense mutation Trp453Stop is located within a putative N-myristoylation site (GCEWNR).
Point mutations were present in eight families, that included 20 patients (Table 2). The patients of family IT-020 with a truncating mutation on one allele and a missense mutation on the other allele were classified in the missense mutation group, assuming that missense mutations may be less deleterious if they result in only partial loss of function of the parkin protein, thereby determining the severity of the illness. Accordingly, the patients of the families for whom only one heterozygous mutation could be detected were included among the truncating (UK-086) or missense mutations (DE-012 and IT-015). The 11 patients with homozygous exon deletions of the parkin gene [three previously published families (18) and family IT-005], the 11 patients with missense mutations (four families) and the nine patients with truncating mutations (four families) showed an overall phenotype of early onset parkinsonism (Table 2). Mean age at onset was 38 ± 12, ranging from 7 to 58. Parkinsonian rigidity (97%) and bradykinesia (97%) were almost always present, whereas tremor was observed in only 68%. These features were associated with dystonia at onset in 30% and with brisk reflexes in the lower limbs without a Babinski sign in 33%. After a mean disease duration of 16 ± 8 years, dyskinesias and fluctuations were present in 71 and 50%, respectively. The effect of the mutations on age at onset, severity or frequency of signs did not differ significantly among the patients carrying different types of mutations.
The initial report of Kitada et al. describing homozygous deletions of exon 4 or exons 3-7 in four Japanese families (17), our own observation of homozygous deletions of exon 3 or exons 8-9 in two European and one Algerian families (18) and the newly identified exon 4 deletion in an Italian family show that a variety of deletions in the parkin gene can cause autosomal recessive parkinsonism, with age at onset as late as 58, as observed in the Italian family IT-005 (Fig. 1). However, it was suspected that other types of mutations (e.g. point mutations) might be a more common cause of the disease (18). The only point mutations reported to date were two homozygous single base pair substitutions in two consanguineous Turkish families, which resulted in a Thr240Arg missense mutation in exon 6 and an Ala311Stop nonsense mutation in exon 8. Until now, however, it could not be determined whether point mutations in the parkin gene account for a significant proportion of autosomal recessive early onset parkinsonism.
Taken together, our three families with previously reported exon deletions (18) and the nine families with mutations detected in the present study demonstrate that mutations in the parkin gene are the cause of the disease in ~30% of the families with autosomal recessive parkinsonism analysed (12/38), including 11 of 35 from Europe. Point mutations were detected in two-thirds of our families (eight of 12 families) and thus seem to be more frequent than homozygous exon deletions (four of 12 families).
The fact that a second mutation could not be detected in families DE-012, IT-015 and UK-086 (which were heterozygous for only one mutation) suggests the presence of a complementary mutation that could not be detected by the techniques used in this study. This second mutation might be located in regions of the gene that were not sequenced (e.g. the promotor region) or might be present as a heterozygous exon deletion that cannot be analysed by simple PCR amplification. However, in order to estimate the frequency of compound heterozygotes resulting from the combination of a point mutation and an exon deletion or of two different exon deletions, we compared the frequencies of the homozygous exon deletions (n = 4) and the homozygous point mutations (n = 4) in eight families with known or suspected consanguinity. The frequency for the two types of homozygous mutations was 50% each in this sample. The frequency of compound heterozygotes for each of the two combinations (deletion + point mutation or deletion + deletion) could therefore reach up to 25%. However, the small sample size precludes accurate estimation of these frequencies.
Only one of the point mutations, the 202-203delAG frameshift, was found in two families of different origins (Italy and UK), suggesting that the mutation occurred independently. Although the patients from these families shared two frequent alleles for the PARK2 markers D6S411 (allele 2 = 59%) and D6S1550 (allele 2 = 68%), the alleles for two other tightly linked markers, D6S305 and D6S1579, were different (data not shown), indicating that a recent common founder effect is unlikely.
All the point mutations are novel and show that a wide variety of different mutations in the parkin gene can account for the disease. The pathogenic role of the point mutations was shown by: (i) co-segregation of the mutations with the disorder in the families; and (ii) their absence in a large number of control chromosomes (110-166 depending on the mutation). All the point mutations identified are likely to have major functional consequences. The four truncating mutations (202-203delAG, 255delA, 321-322insGT and Trp453Stop), which were detected in the homozygous state in three of five families, clearly cause a loss of function of the parkin protein, compatible with a recessive mode of inheritance. Three of the missense mutations result in non-conservative amino acid changes (Lys161Asn, Arg256Cys and Arg275Trp). In family IT-020, the 202-203delAG frameshift mutation on one allele, which results in a loss of function, is associated with an apparently deleterious Lys161Asn missense mutation on the other allele. The conservative Thr415Asn amino acid change, which involves neutral amino acids with different polar side chains, homozygous in all five patients of family IT-014, is located within two consensus sequences of different protein kinases (cAMP- and cGMP-dependent protein kinases and protein kinase C) and might alter post-translational modifications. In addition, codon 415 is located very close to the first cysteine of the RING-finger motif (codon 418) and could affect its structure.
The mutations, which had different effects on the parkin protein, were distributed over six exons, excluding a mutational hotspot. It is interesting to note that, in contrast to the reported Gln311Stop mutation (19), the truncating point mutations identified in this study correspond to the N- and C-terminal regions of the parkin protein (ubiquitin-like and RING-finger motif, respectively), whereas the missense mutations affect the more central regions of the protein, as does the Thr240Arg mutation (19). The previously described ubiquitin-like and RING-finger domains were not affected by the missense mutations. The C-terminal region appears to be extremely important since a homozygous Trp453Stop nonsense mutation, which only removes the last 12 C-terminal residues, causes the disease, perhaps by altering an N-myristoylation site between codons 450 and 455, which prevents a necessary post-translational modification of the protein. The absence of significant clinical differences in this study among the patients with different types of mutations suggests that the modified amino acids are all of functional importance and that their replacement, like the truncating mutations, causes loss of function. The location of the mutations may therefore point to unknown functional domains.
The phenotype of the families with point mutations in the parkin gene and those with exon deletions covered a clinical spectrum that was broader than in the Japanese families originally described (17,19) and is often very close to that of idiopathic PD (Table 2). Mean age at onset (38 years) was that of early onset PD. In 13 patients, however, onset occurred after age 40. Dystonia or brisk reflexes were less frequent than previously reported (10,19). Overall, the phenotypes of patients classified according to the effect of the mutations on the parkin protein were similar, although earlier ages at onset (7-18 years) were observed in the Algerian family with deletion of exons 8 and 9 (18). Similar early onset was also observed in the Japanese family with deletion of exons 3-7 (17) as well as in the patient with the Gln311Stop mutation (19), raising the question of the functional consequences of exon deletions and truncating events in specific regions of the parkin protein, especially as onset within our patients group with truncating mutations was later (between 27 and 53 years).
Finally, three exonic variants (Ser167Asn, Val380Leu and Asp394Asn) were classified as polymorphisms, since they were detected at different frequencies (between 1 and 16%) on control chromosomes. In some families, they did not segregate with the disease. Furthermore, they were found in a family in which the disease was explained by other mutations (the polymorphism Ser167Asn in family IT-020) or were homozygous in healthy controls (Val380Leu and Asp394Asn). They are therefore insufficient to cause the disease by themselves. They might, however, alter the function of the parkin protein and contribute to the pathogenesis of idiopathic PD. Association studies will help to clarify this question.
In conclusion, this study shows that point mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and seem to be more frequent than the exon deletions so far described. Furthermore, the mutations in the parkin gene are associated with a wide range of ages at onset as well as of clinical signs and can result in familial parkinsonism clinically indistinguishable from idiopathic PD. The mutations detected are diverse in their effects on the parkin protein as well as in their localization within the gene. The diversity of the mutations and the absence of a mutational hotspot will complicate molecular diagnosis, but the evident importance of the amino acids affected will help to analyse the function, still unknown, of the parkin protein.
Thirty-eight families were selected according to the following criteria: (i) presence of parkinsonism with good response to levodopa ([ge]30% improvement) in at least two siblings and absence of excluding criteria such as extensor plantar reflexes, ophthalmoplegia, early (after 2 years of disease evolution) dementia or autonomic failure; (ii) onset at [le]45 years in at least one of the siblings; and (iii) inheritance compatible with autosomal recessive transmission (several patients in a single generation with or without known consanguinity). The families originated from France (n = 12), Italy (n = 10), Germany (n = 7), Great Britain (n = 4), Algeria (n = 1), Morocco (n = 1), The Netherlands (n = 1), Portugal (n = 1) and Vietnam (n = 1). Four families from Algeria, France, Italy and Portugal were excluded from sequence analysis because they were found to carry homozygous deletions of either exon 3 or exons 8-9 (18) or exon 4 (family IT-005).
The patients and unaffected relatives were examined by us in one of the movement disorder clinics of the European Consortium on Genetic Susceptibility in Parkinson’s Disease or the French Parkinson’s Disease Genetics Study Group, according to a standardized protocol using the same inclusion and exclusion criteria. All patients were videotaped and the clinical data were centralized. The Kruskal-Wallis test was used for comparisons of means and the [chi]2 test for comparison of frequencies (Yates corrected). Blood samples were taken with informed consent from the patients and their first degree relatives.
The 12 coding exons of the parkin gene from 35 index patients were amplified from genomic DNA by PCR as described by Kitada et al. (17). In family IT-005, an additional pair of exonic primers was used for exon 3 (Ex3iFor, 5[prime]-AATTGTGACCTGGATCAGC-3[prime]; Ex3iRev, 5[prime]-CTGGACTTCCAGCTGGTGGTGAG-3[prime]). For exons 4 and 7 only the intronic primer pairs were used. The same primers were used for the sequencing of the PCR products of the 12 exons on both strands using the Big Dye Terminator Cycle Sequencing Ready Reaction DNA Sequencing kit (Applied Biosystems, Foster City, CA), according to the manufacturer’s recommendations, on an ABI 377 automated sequencer with the Sequence Analysis v.3.0 (Applied Biosystems) software.
Each time a nucleotide variant was identified in an index case, its co-segregation with the disease was established in the patient’s family and its frequency was determined in 36-90 controls (with or without other neurological diseases). Three different techniques were used to detect mutations in the PCR products corresponding to the different exons: (i) allele-specific oligonucleotides (ASOs) to detect the wild-type and the variant sequence; (ii) digestion with the appropriate restriction endonuclease; or (iii) PAGE (Table 1). Nucleotide positions were determined according to the cDNA sequence published in the DNA Data Bank of Japan (DDBJ accession no. AB009973).
Ten microlitres of the PCR product were blotted onto Hybond N+ nylon membranes (Amersham Life Science, Little Chalfont, UK) after denaturation at 95°C for 5 min and fixed in a microwave oven at 600 W for 2 min. For exon 3, the primers Ex3iFor and Ex3iRev were used. The oligonucleotides (Table 3), labeled with [32P]CTP using the Terminal Transferase kit (Boehringer Mannheim, Mannheim, Germany), were hybridized to the membrane at 44°C overnight in a buffer consisting of 5× SSPE, 5× Denhardt’s and 0.1% SDS. The membranes were washed twice for 30 min in 2× SSC at 59°C and exposed to MP film (Amersham) for 3-6 h.
Fifteen microlitres of PCR product were digested with restriction enzymes according to the manufacturer’s recommendations. The expected fragment lengths are given in Table 1.
A 5[prime]-fluorescent (Hex) forward primer (17) was used to amplify exon 2. The presence of the 202-203delAG variant, resulting in a shorter PCR product (306 versus 308 bp), was established by fragment size measurement using an ABI 377 automated sequencer with the Genescan v.2.0.2 and Genotyper v.1.1.1 software (Applied Biosystems).
We thank the families for their participation, and Merle Ruberg for helpful discussions. This work was supported by the AP-HP, the Association France-Parkinson, MURST (Italian Ministry for University, Scientific and Technological Research) and the European Community Biomed 2 (BMH4CT960664).
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